Evaluation on performance of MM/PBSA in nucleic acid-protein systems

The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method has been widely used in predicting the binding affinity among ligands, proteins, and nucleic acids. However, the accuracy of the predicted binding energy by the standard MM/PBSA is not always good, especially in highly charged systems. In this work, we take the protein-nucleic acid complexes as an example, and showed that the use of screening electrostatic energy (instead of Coulomb electrostatic energy) in molecular mechanics can greatly improve the performance of MM/PBSA. In particular, the Pearson correlation coefficient of dataset II in the modified MM/PBSA (i.e., screening MM/PBSA) is about 0.52, much better than that (< 0.33) in the standard MM/PBSA. Further, we also evaluate the effect of solute dielectric constant and salt concentration on the performance of the screening MM/PBSA. The present study highlights the potential power of the screening MM/PBSA for predicting the binding energy in highly charged bio-systems.     

Accurate Evaluation on the Interactions of SARS-CoV-2 with Its Receptor ACE2and Antibodies CR3022/CB6

The spread of the coronavirus disease 2019(COVID-19) caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2) has become a global health crisis.The binding affinity of SARS-CoV-2(in particular the receptor binding domain,RBD) to its receptor angiotensin converting enzyme 2(ACE2) and the antibodies is of great importance in understanding the infectivity of COVID-19 and evaluating the candidate therapeutic for COVID-19.We propose a new method based on molecular mechanics/Poisson-Boltzmann surface area(MM/PBSA) to accurately calculate the free energy of SARS-CoV-2 RBD binding to ACE2 and antibodies.The calculated binding free energy of SARS-CoV-2 RBD to ACE2 is-13.3 kcal/mol,and that of SARS-CoV RBD to ACE2 is-11.4 kcal/mol,which agree well with the experimental results of-11.3 kcal/mol and-10.1 kcal/mol,respectively.Moreover,we take two recently reported antibodies as examples,and calculate the free energy of antibodies binding to SARS-CoV-2 RBD,which is also consistent with the experimental findings.Further,within the framework of the modified MM/PBSA,we determine the key residues and the main driving forces for the SARS-CoV-2 RBD/CB6 interaction by the computational alanine scanning method.The present study offers a computationally efficient and numerically reliable method to evaluate the free energy of SARS-CoV-2 binding to other proteins,which may stimulate the development of the therapeutics against the COVID-19 disease in real applications.